P1663: LYSINE-CONTAINING OLIGOPEPTIDES CAN INCREASE FIBRINOLYTIC ACTIVITY
Authors: Tatiana Shubina, Marina Grigorjeva, Tamara Obergan, Ludmila Lyapina
Journal: HemaSphere (2023)

Topic: 34. Thrombosis and vascular biology - Biology & Translational Research Background: Atherosclerotic vascular changes are observed in violation of the lipid profile, carbohydrate metabolism and increased blood clotting, which may be associated with the development of metabolic syndrome (MS) in the body. This pathology is accompanied by endothelial dysfunction, which is manifested by a decrease in fibrinolytic activity due to reduce in the activity of the tissue plasminogen activator. Natural regulatory peptides are used in the development of drugs that promote the inclusion of compensatory and adaptive reactions of the body in damage of homeostatic balance. On their basis, new synthetic peptides of the glyproline series were synthesized. For them, the ability to exert regulatory effects on the processes of coagulation and fibrinolysis in normal and in various pathological conditions was shown. Aims: To identify the effect of lysine-containing oligopeptides Arg-Lys-Lys-Arg-Pro-Gly-Pro (RKKRPGP) and Lys-Arg-Arg-Lys-Pro-Gly-Pro (KRRKPGP) on the state of the fibrinolytic system in violation of lipid and carbohydrate metabolism in various ways of their introduction into the body. Methods: The peptides RKKRPGP and KRRKPGP used were synthesized at the Institute of Molecular Genetics of the Russian Academy of Sciences. The experiments were carried out on healthy male laboratory rats of the Wistar line, weighing 300-400 g, as well as animals of the same line, but with metabolic syndrome (MS), which was induced by a high-calorie diet, and verified by changes in the lipid profile and the presence of obesity. In the I-th series of experiments, healthy animals of the 1st group (1a- RKKRPGP; 1b- KRRKPGP) were injected with peptides intranasally, and the 2nd - (2a and 2b - similarly) - orally at a daily dose of 100 mg/kg for 7 days once a day. In the II-nd series of experiments, peptides were administered intranasally to rats with MS according to a similar scheme. Each group had its own control (0.85% NaCl solution was administered). Blood sampling was performed from v. jugularis 20 h after the last administration of the peptide. All experiments were carried out in accordance with the Helsinki Declaration. In platelet-poor plasma, biochemical parameters were determined: spontaneous euglobulin lysis (SEL), total fibrinolytic activity (TFA), the activity of tissue plasminogen activator (t-PA), plasmin activity (PA), and in MS animals, the blood glucose level was additionally determined. Results: It was found that in groups 1 and 2, the SEL was shortened by an average of 30-40% compared to the control. With the introduction of KRRKPGP, an increase in TFА was observed: in group 1b due to the activity of t-PA and PA, in group 2b - only due to an increase in PA. In the II-nd series of experiments, it was found that the administration of both peptides to rats with MS reduces blood glucose levels by 20% and increases the fibrinolytic activity of blood plasma of rats with MS, compensating for hypercoagulation observed in control animals. Thus, SEL and PA corresponded to the norm, and TFA and t-PA activity increased by 40% and 24%, respectively, compared with the control. Summary/Conclusion: Administration of peptides RKKRPGP and KRRKPGP to healthy animals and rats with MS demonstrates activation of vascular endothelial function (increased t-PA), which leads to a decrease in the prothrombotic status of the organism. Thus, the investigated new lysine-containing oligopeptides, with the tripeptide glyproline group prolyl-glycyl-prolyl from the C-end, can be attributed to promising substances with fibrinolytic action. Keywords: Fibrinolysis, Blood coagulation, tPA, Animal model